Methylmercury (MeHg) is a potent environmental toxin that preferentially causes damage to the nervous system. Bioaccumulation of MeHg in the aquatic food chain poses a significant risk to humans through dietary intake of fresh and saltwater fish. Recent evidence has established that the fetal brain is the most highly susceptible target organ in MeHg poisoning. However, mechanisms of MeHg toxicity that are specific to the developing nervous system are not well understood. We will investigate mechanisms of MeHg toxicity with the overall hypothesis that MeHg impairs function of receptor signaling pathways in neural development. Our recent studies support this hypothesis by elucidating a novel and direct activity of MeHg to induce proteolysis of the Notch receptor and its ligand, Delta. Notch and Delta are highly conserved cell surface signaling proteins that dictate cell fate decisions and regulate neurite outgrowth in neural development. This novel mechanism involves MeHg-induced activation of latent ADAM (a disintegrin and metalloprotease) cell surface proteases through a cysteine switch mechanism. ADAMs regulate Notch signals by promoting cleavages in the Notch and Delta proteins. ADAMs are known to act in a similar fashion on several other cell surface receptors and ligands that are central to neural development. Our two main objective are: 1) to determine how MeHg alters the Notch and Delta proteins and their signaling activity in the developing nervous system, and 2) to identify additional neuron-specific signaling pathway proteins that are altered by MeHg-induced proteolysis. We will use a multidisciplinary approach consisting of biochemical and cell-based assays in both cultured neurons and in vivo in a Drosophila model system. Our analyses will identify the critical signaling pathways in neural development that are targets for MeHg-induced damage. This information will help direct strategies for prevention of MeHg toxicity, for example through pharmacologic administration of protease inhibitors.